1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a commercially available compound that can be formed as a by-product in the synthesis of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). MPPP is a potent analgesic agent structurally similar to other widely used analgesic agents including meperidine and alphaprodine. It was recently reported that the inadvertent ingestion of small amounts of MPTP, mixed with varying amounts of MPPP and perhaps other agents, caused an irreversible Parkinsonism in several young individuals, who were most likely attempting to simulate the actions of heroin with MPPP. It has also been reported that the injections of MPTP alone to mondeys caused symptoms and pathology consistent with Parkinsonism, including a servere dopamine depletion and destruction of the substantia nigra. It thus appears likely that the agent responsible for the Parkinsonism observed in the young drug addicts was MPTP or a metabolite. The discovery that a simple substance of this nature administered systemically can reproduce so closely the pathology of Parkinson's disease has enormous implications for the etiology of the naturally occurring human disease. It suggests that a similar neurotoxin, exogenous or endogenous, may be involved in the pathogenesis of the disease. It has been reported by others that MPTP could not produce symptoms of Parkinson's disease in other species including rats and cats. However, we have discovered that MPTP administration to mice (two to ten daily injections) produces features of dopaminergic neuronal destruction, including large and long-lasting decrements in neostriatal levels of dopamine and its metabolites and in the capacity of neostriatal brain tissue to accumulate 3H-dopamine. In the present research project, we hope to expand on our findings and to develop the MPTP treated mouse as an animal model for Parkinson's disease. A second and more important goal is to learn as much as possible about the basic features of the action of MPTP and many of its structural analogs. Since all of these findings with MPTP are relatively recent and so little is known about MPTP, anything that we discover concerning the actions of MPTP can potentially be important. It is hoped that we will be able to determine the exact mode of action of MPTP. An overall goal underlying this entire project is to determine if there are similarities in the etiology of Parkinsonism caused in experimental animals by MPTP and the etiology of idiopathic Parkinsonism in humans.